tbuckley/cabot-search huggingface dataset:
Clinical response in the haustra-like folds observed during peroral cholangioscopy following steroid therapy for immune checkpoint inhibitor-induced cholangitis
Authors: Yoshiya Takeda, Osamu Inatomi, Shuhei Shintani, Takehide Fujimoto, Atsushi Nishida, Hiromu Kutsumi, Akira Andoh
Journal: Endoscopy (2022)

Immune-related adverse event (AE) cholangitis caused by immune checkpoint inhibitors is relatively rare (0.05 %–3.3 %), and steroids are an effective treatment [1]. Although some papers have reported the characteristic findings on peroral direct cholangioscopy [2], it is still unclear how to taper the steroid dose to best improve the condition.
Change of Article Status to Open Access
Authors: Bishal Gyawali, Elizabeth Eisenhauer, Michael Brundage
Journal: JAMA Oncology (2022)

Michael L. Chen, BA; Isabella Joy de Vere Hunt, MD; Esther M. John, PhD, MSPH; Martin A. Weinstock, MD, PhD; Susan M. Swetter, MD; Eleni Linos, MD, DrPH
World Health Organization 2021 Classification of Central Nervous System Tumors and Implications for Therapy for Adult-Type Gliomas
Authors: Tamar R. Berger, Patrick Y. Wen, Melanie Lang-Orsini, Ugonma N. Chukwueke
Journal: JAMA Oncology (2022)

Importance Previous histologic classifications of brain tumors have been limited by discrepancies in diagnoses reported by neuropathologists and variability in outcomes and response to therapies. Such diagnostic discrepancies have impaired clinicians’ ability to select the most appropriate therapies for patients and have allowed heterogeneous populations of patients to be enrolled in clinical trials, hindering the development of more effective therapies. In adult-type diffuse gliomas, histologic classification has a particularly important effect on clinical care. Observations In 2021, the World Health Organization published the fifth edition of the Classification of Tumors of the Central Nervous System. This classification incorporates advances in understanding the molecular pathogenesis of brain tumors with histopathology in order to group tumors into more biologically and molecularly defined entities. As such, tumor classification is significantly improved through better characterized natural histories. These changes have particularly important implications for gliomas. For the first time, adult- and pediatric-type gliomas are classified separately on the basis of differences in molecular pathogenesis and prognosis. Furthermore, the previous broad category of adult-type diffuse gliomas has been consolidated into 3 types: astrocytoma, isocitrate dehydrogenase ( IDH ) mutant; oligodendroglioma, IDH mutant and 1p/19q codeleted; and glioblastoma, IDH wild type. These major changes are driven by IDH mutation status and include the restriction of the diagnosis of glioblastoma to tumors that are IDH wild type; the reclassification of tumors previously diagnosed as IDH -mutated glioblastomas as astrocytomas IDH mutated, grade 4; and the requirement for the presence of IDH mutations to classify tumors as astrocytomas or oligodendrogliomas. Conclusions and Relevance The 2021 World Health Organization central nervous system tumor classification is a major advance toward improving the diagnosis of brain tumors. It will provide clinicians with more accurate guidance on prognosis and optimal therapy for patients and ensure that more homogenous patient populations are enrolled in clinical trials, potentially facilitating the development of more effective therapies.
Inflammatory pathways in heart failure with preserved left ventricular ejection fraction: implications for future interventions
Authors: Nicola Riccardo Pugliese, Pierpaolo Pellicori, Francesco Filidei, Nicolò De Biase, Pasquale Maffia, Tomasz J Guzik, Stefano Masi, Stefano Taddei, John G F Cleland
Journal: Cardiovascular Research (2022)

Abstract Many patients with symptoms and signs of heart failure have a left ventricular ejection fraction ≥50%, termed heart failure with preserved ejection fraction (HFpEF). HFpEF is a heterogeneous syndrome mainly affecting older people who have many other cardiac and non-cardiac conditions that often cast doubt on the origin of symptoms, such as breathlessness, or signs, such as peripheral oedema, rendering them neither sensitive nor specific to the diagnosis of HFpEF. Currently, management of HFpEF is mainly directed at controlling symptoms and treating comorbid conditions such as hypertension, atrial fibrillation, anaemia, and coronary artery disease. HFpEF is also characterized by a persistent increase in inflammatory biomarkers. Inflammation may be a key driver of the development and progression of HFpEF and many of its associated comorbidities. Detailed characterization of specific inflammatory pathways may provide insights into the pathophysiology of HFpEF and guide its future management. There is growing interest in novel therapies specifically designed to target deregulated inflammation in many therapeutic areas, including cardiovascular disease. However, large-scale clinical trials investigating the effectiveness of anti-inflammatory treatments in HFpEF are still lacking. In this manuscript, we review the role of inflammation in HFpEF and the possible implications for future trials.
Response to Comment on “Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases”
Authors: Xianyuan Xiang, Sabina Tahirovic, Sibylle Ziegler, Christian Haass, Matthias Brendel
Journal: Science Translational Medicine (2022)

Microglial FDG uptake alterations are the source of FDG-PET changes in models of neurodegenerative diseases.
Comment on “Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases”
Authors: Eduardo R. Zimmer, Tharick A. Pascoal, Pedro Rosa-Neto, Agneta Nordberg, Luc Pellerin
Journal: Science Translational Medicine (2022)

Astrocytes might be the major contributor to the radioactive signal captured by PET in the microglia-dependent modulation of FDG-PET.
Global Consumption Trend of Antifungal Agents in Humans From 2008 to 2018: Data From 65 Middle- and High-Income Countries
Authors: Swathi Pathadka, Vincent K. C. Yan, Chin Fen Neoh, Daoud Al-Badriyeh, David C. M. Kong, Monica A. Slavin, Benjamin J. Cowling, Ivan F. N. Hung, Ian C. K. Wong, Esther W. Chan
Journal: Drugs (2022)

Understanding the trend of global antifungal agent consumption could assist with identification of global healthcare policy inadequacies and promote accessibility and availability of antifungal agents. Using pharmaceutical sales data from the IQVIA-multinational integrated data analysis system database, we assessed use of systemic antifungal agents in humans in 27 middle- and 38 high-income countries from 2008 through 2018. Consumption of systemic antifungal agents increased from 0.50 (in 2008) to 0.92 defined daily dose (DDD)/1000 inhabitants/day (in 2018), with a compound annual growth rate of 6.2%. High-income countries remain major consumers of antifungal agents with large variance in quantities consumed, with a gradual decline in consumption in recent years. Consumption in middle-income countries increased. Itraconazole (0.32 DDD/1000 inhabitants/day), terbinafine (0.30 DDD/1000 inhabitants/day), and fluconazole (0.23 DDD/1000 inhabitants/day) were the most commonly used antifungal agents in middle- and high-income countries in 2018. Following incorporation into the World Health Organization Essential Medicines List, itraconazole consumption in middle-income countries surged. Consumption of ketoconazole slowly declined, with 5.04% annual decrease, probably due to labelling changes in 2013 to reflect hepatotoxicity concerns. The use of polyenes (0.004 DDD/1000 inhabitants/day) and echinocandins (0.003 DDD/1000 inhabitants/day) were lowest among all the antifungal drug classes. Global consumption of triazoles and terbinafine has gradually increased in middle- and high-income countries. Life-saving antifungal agents, including echinocandins and polyenes, are available only parenterally and may be underutilized, mainly in middle-income countries. Future research on country-specific epidemiology is warranted to guide health policy coordination to ensure equitable access to appropriate use of antifungal agents.
Olokizumab versus Placebo or Adalimumab in Rheumatoid Arthritis
Authors: Josef S. Smolen, Eugen Feist, Saeed Fatenejad, Sergey A. Grishin, Elena V. Korneva, Evgeniy L. Nasonov, Mikhail Y. Samsonov, Roy M. Fleischmann
Journal: New England Journal of Medicine (2022)

The cytokine interleukin-6 is involved in the pathogenesis of rheumatoid arthritis. Olokizumab, a humanized monoclonal antibody targeting the interleukin-6 cytokine directly, is being tested for the treatment of rheumatoid arthritis.In a 24-week, phase 3, multicenter, placebo- and active-controlled trial, we randomly assigned (in a 2:2:2:1 ratio) patients with rheumatoid arthritis and an inadequate response to methotrexate to receive subcutaneous olokizumab at a dose of 64 mg every 2 or 4 weeks, adalimumab (40 mg every 2 weeks), or placebo; all patients continued methotrexate therapy. The primary end point was an American College of Rheumatology 20 (ACR20) response (≥20% fewer tender and swollen joints and ≥20% improvement in three of five other domains) at week 12, with each olokizumab dose tested for superiority to placebo. We also tested the noninferiority of each olokizumab dose to adalimumab with respect to the percentage of patients with an ACR20 response (noninferiority margin, -12 percentage points in the lower boundary of the 97.5% confidence interval for the difference between groups).A total of 464 patients were assigned to receive olokizumab every 2 weeks, 479 to receive olokizumab every 4 weeks, 462 to receive adalimumab, and 243 to receive placebo. An ACR20 response at week 12 occurred in 44.4% of the patients receiving placebo, in 70.3% receiving olokizumab every 2 weeks (difference vs. placebo, 25.9 percentage points; 97.5% confidence interval [CI], 17.1 to 34.1), in 71.4% receiving olokizumab every 4 weeks (difference vs. placebo, 27.0 percentage points; 97.5% CI, 18.3 to 35.2), and in 66.9% receiving adalimumab (difference vs. placebo, 22.5 percentage points; 95% CI, 14.8 to 29.8) (P<0.001 for the superiority of each olokizumab dose to placebo). Both olokizumab doses were noninferior to adalimumab with respect to the percentage of patients with an ACR20 response at week 12 (difference, 3.4 percentage points [97.5% CI, -3.5 to 10.2] with olokizumab every 2 weeks and 4.5 percentage points [97.5% CI, -2.2 to 11.2] with olokizumab every 4 weeks). Adverse events, most commonly infections, occurred in approximately 70% of the patients who received olokizumab. Antibodies against olokizumab were detected in 3.8% of the patients receiving the drug every 2 weeks and in 5.1% of those receiving it every 4 weeks.In patients with rheumatoid arthritis who were receiving maintenance methotrexate, olokizumab was superior to placebo and noninferior to adalimumab in producing an ACR20 response at 12 weeks. Larger and longer trials are required to determine the efficacy and safety of olokizumab in patients with rheumatoid arthritis. (Supported by R-Pharm; CREDO2 ClinicalTrials.gov number, NCT02760407.).
Saline-immersion therapeutic endoscopy facilitated en bloc endoscopic submucosal-subserosal dissection of a sigmoid diverticulum containing a refractory adenomatous lesion
Authors: Nikolaos Lazaridis, Stavroula Pelitari, Alberto Murino, Yoshikazu Hayashi, Hironori Yamamoto, Edward J. Despott
Journal: Endoscopy (2022)

Underwater resection has become a well-recognized alternative approach to standard endoscopic resection techniques [1]. Based on the same principles, saline-immersion therapeutic endoscopy (SITE) was introduced as an "evolution of the underwater technique" with several potential advantages [2]. SITE facilitates endoscopic submucosal dissection (ESD) through maintenance of the submucosal lift, intrinsic buoyancy (obviating the need for traction), enhanced dissection, and improved visibility [2] [3].
Preclinical evaluation of proteolytic targeting of LCK as a therapeutic approach in T cell acute lymphoblastic leukemia
Authors: Jianzhong Hu, Jamie Jarusiewicz, Guoqing Du, Gisele Nishiguchi, Satoshi Yoshimura, John C. Panetta, Zhenhua Li, Jaeki Min, Lei Yang, Divyabharathi Chepyala, Marisa Actis, Noemi Reyes, Brandon Smart, Ching-Hon Pui, David T. Teachey, Zoran Rankovic, Jun J. Yang
Journal: Science Translational Medicine (2022)

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and there is an unmet need for targeted therapies, especially for patients with relapsed disease. We have recently identified pre-T cell receptor and lymphocyte-specific protein tyrosine kinase (LCK) signaling as a common therapeutic vulnerability in T-ALL. LCK inhibitor dasatinib showed efficacy against T-ALL in preclinical studies and in patients with T-ALL; however, this is transient in most cases. Leveraging the proteolysis targeting chimera (PROTAC) approach, we developed a series of LCK degraders using dasatinib as an LCK ligand and phenyl-glutarimide as a cereblon-directing moiety. Our lead compound SJ11646 exhibited marked efficiency in cereblon-mediated LCK degradation in T-ALL cells. Relative to dasatinib, SJ11646 showed up to three orders of magnitude higher cytotoxicity in LCK-activated T-ALL cell lines and primary leukemia samples in vitro, with drastically prolonged suppression of LCK signaling. In vivo pharmacokinetic and pharmacodynamic profiling indicated a 630% increase in the duration of LCK suppression by SJ11646 over dasatinib in patient-derived xenograft models of T-ALL, which translated into its extended leukemia-free survival over dasatinib in vivo. Last, SJ11646 retained a high binding affinity to 51 human kinases, particularly ABL1, KIT, and DDR1, all of which are known drug targets in other cancers. Together, our dasatinib-based phenyl-glutarimide PROTACs are promising therapeutic agents in T-ALL and valuable tools for developing degradation-based therapeutics for other cancers.
Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment
Authors: Yibo Fan, Yuan Li, Xiaodan Yao, Jiangkang Jin, Ailing Scott, Bovey Liu, Shan Wang, Longfei Huo, Ying Wang, Ruiping Wang, Melissa Pool Pizzi, Lang Ma, Shan Shao, Matheus Sewastjanow-Silva, Rebecca Waters, Deyali Chatterjee, Bin Liu, Namita Shanbhag, Guang Peng, George Adrian Calin, Pawel Karol Mazur, Samir M Hanash, Jo Ishizawa, Yuki Hirata, Osamu Nagano, Zhenning Wang, Linghua Wang, Wa Xian, Frank McKeon, Jaffer A Ajani, Shumei Song
Journal: Gut (2022)

Objective Many cancers engage embryonic genes for rapid growth and evading the immune system. SOX9 has been upregulated in many tumours, yet the role of SOX9 in mediating immunosuppressive tumour microenvironment is unclear. Here, we aim to dissect the role of SOX9-mediated cancer stemness attributes and immunosuppressive microenvironment in advanced gastric adenocarcinoma (GAC) for novel therapeutic discoveries. Methods Bulk RNAseq/scRNA-seq, patient-derived cells/models and extensive functional studies were used to identify the expression and functions of SOX9 and its target genes in vitro and in vivo. Immune responses were studied in PBMCs or CD45 + immune cells cocultured with tumour cells with SOX9 high or knockout and the KP-Luc2 syngeneic models were used for efficacy of combinations. Results SOX9 is one of the most upregulated SOX genes in GAC and highly expressed in primary and metastatic tissues and associated with poor prognosis. Depletion of SOX9 in patient-derived GAC cells significantly decreased cancer stemness attributes, tumour formation and metastases and consistently increased CD8 + T cell responses when cocultured with PBMCs/CD45 + cells from GAC patients. RNA sequencing identified the leukaemia inhibitory factor (LIF) as the top secreted molecule regulated by SOX9 in tumour cells and was enriched in malignant ascites and mediated SOX9-induced M2 macrophage repolarisation and inhibited T cell function. Conclusion Epithelial SOX9 is critical in suppressing CD8 + T cell responses and modified macrophage function in GAC through the paracrine LIF factor. Cotargeting LIF/LIFR and CSF1R has great potential in targeting SOX9-mediated cancer stemness, T cell immunosuppression and metastases suggesting the novel combination therapy against advanced GAC.
Multipolar traction with adjustable force increases procedure speed during endoscopic submucosal dissection: the A-TRACT-4 traction device
Authors: Jean Grimaldi, Louis-Jean Masgnaux, Jérôme Rivory, Romain Legros, Timothée Wallenhorst, Jérémie Jacques, Mathieu Pioche
Journal: Endoscopy (2022)

A major barrier to the more widespread use of endoscopic submucosal dissection (ESD) remains the long-lasting duration of the procedure compared to piecemeal endoscopic mucosal resection (EMR). Several devices and techniques have been described to speed and ease the procedure [1], and traction strategies are implemented more and more to improve efficiency of the dissection phase.
The human gut serves as a reservoir of hypervirulent <i>Klebsiella pneumoniae</i>
Authors: Jing Yang, Yi Li, Na Tang, Juan Li, Juan Zhou, Shan Lu, Gui Zhang, Yuqin Song, Chao Wang, Jin Zhong, Jianguo Xu, Jie Feng
Journal: Gut Microbes (2022)

Hypervirulent Klebsiella pneumoniae (hvKp) can cause serious infections and has been increasingly reported clinically. However, we still lack the knowledge to what degree hvKp colonize the community. In this study, we investigated colonization of hvKp in healthy human gut and the relationship between gut hvKp and clinically important invasive strains. We compile global genomes of gut K. pneumoniae for in-depth genetic analysis and found most hvKp genomes originated from Chinese datasets; therefore, we collected gut K. pneumoniae isolates from healthy people around China. The results revealed a moderate carriage rate of hvKp in the healthy population (4%–5.19%). Phylogenetic analysis indicated a close relationship between gut hvKp and fatal clinical strains. These results demonstrate that the human gut may serve as a reservoir of hvKp and that gut hvKp can play a role in infection of other body parts.
Immune dysregulation caused by homozygous mutations in CBLB
Authors: Erin Janssen, Zachary Peters, Mohammed F. Alosaimi, Emma Smith, Elena Milin, Kelsey Stafstrom, Jacqueline G. Wallace, Craig D. Platt, Janet Chou, Yasmeen S. El Ansari, Tariq Al Farsi, Najim Ameziane, Ruslan Al-Ali, Maria Calvo, Maria Eugenia Rocha, Peter Bauer, Nouriya Abbas Al-Sannaa, Nashat Faud Al Sukaiti, Abdullah A. Alangari, Aida M. Bertoli-Avella, Raif S. Geha
Journal: Journal of Clinical Investigation (2022)

CBL-B is an E3 ubiquitin ligase that ubiquitinates proteins downstream of immune receptors to downregulate positive signaling cascades. Distinct homozygous mutations in CBLB were identified in 3 unrelated children with early-onset autoimmunity, one of whom also had chronic urticaria. Patient T cells exhibited hyperproliferation in response to anti-CD3 cross-linking. One of the mutations, p.R496X, abolished CBL-B expression, and a second mutation, p.C464W, resulted in preserved CBL-B expression. The third mutation, p.H285L in the SH2 domain of CBL-B, was expressed at half the normal level in the patient's cells. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient's p.H285L mutation, had T and B cell hyperproliferation in response to antigen receptor cross-linking. CblbH257L mice had increased percentages of T regulatory cells (Tregs) that had normal in vitro suppressive function. However, T effector cells from the patient with the p.H285L mutation and CblbH257L mice were resistant to suppression by WT Tregs. Bone marrow-derived mast cells from CblbH257L mice were hyperactivated after FcεRI cross-linking, and CblbH257L mice demonstrated exaggerated IgE-mediated passive anaphylaxis. This study establishes CBL-B deficiency as a cause of immune dysregulation.
Geographic Variation in Appointment Wait Times for US Military Veterans
Authors: Yevgeniy Feyman, Daniel A. Asfaw, Kevin N. Griffith
Journal: JAMA Network Open (2022)

Timely access to medical care is an important determinant of health and well-being. The US Congress passed the Veterans Access, Choice, and Accountability Act in 2014 and the VA MISSION (Maintaining Systems and Strengthening Integrated Outside Networks) Act in 2018, both of which allow veterans to access care from community-based clinicians, but geographic variation in appointment wait times after the passage of these acts have not been studied.
Health Care Utilization Trends Across the Transition Period in a National Cohort of Adolescents and Young Adults With Type 1 Diabetes
Authors: Katharine C. Garvey, Jonathan A. Finkelstein, Fang Zhang, Robert LeCates, Lori Laffel, James F. Wharam
Journal: Diabetes Care (2022)

OBJECTIVE Lack of effective transition from pediatric to adult care may contribute to adverse outcomes in young adults with type 1 diabetes. The understanding of outpatient and acute care utilization patterns across the adolescent to young adult transition age in type 1 diabetes populations is suboptimal in the U.S. RESEARCH DESIGN AND METHODS We studied claims data from 14,616 individuals diagnosed with type 1 diabetes, aged 16–24 years, and enrolled in a large national health plan for ≥1 year from 2005 to 2012. Annual outpatient and emergency department visits and hospitalization rates were calculated at each age. Generalized estimating equations were used to assess the association of age-group (adolescents [age 16–18 years] vs. young adults [age 19–24 years]), outpatient visits, and sociodemographic variables with emergency department visit and hospitalization rates. RESULTS Endocrinologist visits declined from 2.3 per year at age 16 years to 1.5 per year by age 22. Emergency department rates increased per year from 45 per 100 at age 16 to 63 per 100 at age 20, then decreased to 60 per 100 by age 24. Hospitalizations per year climbed from 14 per 100 at age 16 to 21 per 100 at age 19, then decreased to 17 per 100 by age 24. In statistical models, young adults experienced higher rates of emergency department visits (incidence rate ratio [IRR] 1.24 [95% CI 1.18, 1.31]) and hospitalizations (IRR 1.25 [95% CI 1.15, 1.36]) than adolescents. Additional significant predictors of emergency department visits and hospitalizations included female sex and Black race. Individuals with two or more endocrinologist visits per year were less likely to have emergency department visits and hospitalizations; higher income was also protective. CONCLUSIONS Results highlight concerning increases in acute care utilization for young adults with type 1 diabetes who are less engaged with outpatient diabetes care and highlight socioeconomic risk factors that warrant further study.